Antibodies against endogenous retroviruses promote lung cancer immunotherapy
Details
Publication Year 2023-04,Volume 616,Issue #7957,Page 563-573
Journal Title
Nature
Publication Type
Research article
Abstract
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)(1,2). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive(1,2). Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma(3). We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Publisher
Springer Nature
Keywords
Animals; Humans; Mice; Adenocarcinoma of Lung/immunology/therapy/virology; Carcinoma, Non-Small-Cell Lung/immunology/therapy/virology; Disease Models, Animal; *Endogenous Retroviruses/immunology; *Immunotherapy/methods; Lung/immunology; *Lung Neoplasms/immunology/therapy/virology; Tumor Microenvironment; B-Lymphocytes/immunology; Cohort Studies; Antibodies/immunology/therapeutic use
Department(s)
Laboratory Research
PubMed ID
37046094
Open Access at Publisher's Site
https://doi.org/10.1038/s41586-023-05771-9
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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Last Modified: 2023-08-03 08:01:33

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